title: The role of mediators of cell invasiveness, motility, and migration in the pathogenesis of silent corticotroph adenomas.
abstract: Silent corticotroph adenomas (SCAs) represent a distinct subset of clinically non-functioning pituitary adenomas. There are two variants of SCA; type I are densely granulated basophilic tumors and type II are sparsely granulated and chromophobic tumors. SCAs are known to be aggressive than the more common non-functioning gonadotroph adenomas (NFGAs). Cell-matrix interactions play an important role in the pathogenesis of pituitary adenomas. In this study, we compared 19 SCAs and 50 NFGAs with known fibroblast growth factor receptor-4 (FGFR4) status using semi-quantitative immunohistochemistry to localize β1-integrin, osteopontin, and matrix metalloproteinase-1 (MMP-1) as cytoplasmic, membranous, or mixed cytoplasmic-membranous staining to achieve scores of 1-4. Staining for β1-integrin was significantly higher in SCAs (100 %, score 3.3) than in NFGAs (96 %; score 2.6) (p = 0.0482); there was no statistical difference within subgroups of SCA (type II score 3.4; type I score 2.8) (p = 0.2663). Osteopontin immunoreactivity was also higher in SCAs (100 %, score 3.7) than in NFGAs (42 %, score 0.8) (p = 0.0001); there was no statistical difference within subgroups of SCA (type II score 3.6; type I score 3.9) (p = 0.2787). In contrast, MMP-1 immunoreactivity was lower in SCAs (89 %; score 2.5) than in NFGAs (98 %; score 3.6) (p = 0.0005); there was no statistical difference within subgroups of SCA (type II score 2.7; type I score 2.0) (p = 0.30704). The MMP-1 results correlated with FGFR4 expression (NFGA 96 %, type II SCA 71 %, type I SCA 40 %). Our data indicate that the biological aggressivity of SCAs compared with NFGA may be due to high osteopontin expression; in contrast, high MMP-1 is characteristic of NFGAs that also express more FGFR4. Further investigations are warranted to clarify the underlying regulatory mechanisms of these markers. The high osteopontin or FGFR4/MMP-1 expression levels in SCAs and NFGAs, respectively, indicate the potential for therapeutic strategies targeting osteopontin or FGFR4/MMP-1 for inoperable tumors of these types.
authors.affiliation: Department of Pathology, University Health Network, 200 Elizabeth Street, 11th floor, Toronto, ON, M5G 2C4, Canada, ozgur.mete2@uhn.ca.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Mete
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayhurst
authors.forename: Hussein
authors.initials: H
authors.lastname: Alahmadi
authors.forename: Eric
authors.initials: E
authors.lastname: Monsalves
authors.forename: Hasan
authors.initials: H
authors.lastname: Gucer
authors.forename: Fred
authors.initials: F
authors.lastname: Gentili
authors.forename: Shereen
authors.initials: S
authors.lastname: Ezzat
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
mesh_terms: D049913:ACTH-Secreting Pituitary Adenoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D000236:Adenoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D053495:Osteopontin / Q000378:metabolism
chemical_list: C496445:FGF4 protein, human; D051519:Fibroblast Growth Factor 4; D039641:Integrin beta Chains; D053495:Osteopontin; D020781:Matrix Metalloproteinase 1